We continue our collaboration with the Cushman lab (NIDDK) to analyze cell-size distributions in adipose tissue in order to elucidate relationships between fat cell size and insulin resistance. We previously reported that such distributions are roughly bi-model, with a Gaussian peak of large, mature cells and an exponential tail of small cells. In contrast to prior hypotheses, we found that the size of the large fat cells per se is not associated with insulin resistance (IR) when moderately obese subjects are matched for obesity. Rather, we found a correlation between the proportion of large cells and IR, with resistant subjects having a deficit of large cells. We proposed that this reflects an impairment of adipocyte differentiation and leads to insufficient fat storage capacity and ectopic fat deposition in other organs, such as liver, pancreas, and muscle, that are not well equipped to handle large volumes of fat.[unreadable] [unreadable] Additional data now suggest that the deficit of large cells applies to male subjects, but not females. Additional insulin sensitive, moderately obese male subjects are being sought to further test this conclusion.[unreadable] [unreadable] We have also extended these studies to intervention with the insulin sensitizer, pioglitazone. We found that the drug led to an increase of the proportion of small cells, perhaps reflecting increased recruitment of new adipocytes from precursor cells. Although this seems superficially at odds with the previously reported higher proportion of large cells in insulin sensitive subjects, we note that amelioration of insulin resistance by drug treatment does not necessarily restore the metabolic state of an insulin resistant subject to that of a normal subject. Also, it is possible that the newly recruited small cells would eventually accumulate more fat and become large. In support of this, the trends suggest that the drug increased the number of small cells but did not reduce the number of large cells. A manuscript is in preparation.[unreadable] [unreadable] Further cross-sectional study of insulin-sensitive and resistant subjects has examined the relationship between IR and expression of inflammation genes. Some genes associated with inflammation do seem to be associated with IR, and some inflammation genes are associated with a reduced proportion of large cells. The three properties, IR, inflammation, and diminished large-cell proportion, thus seem to have a complex triangular relationship that depends on the gene in question and also on gender. A manuscript is in preparation.